Activation of Toll-like receptor (TLR signaling) by conserved microbial molecular signatures promotes the[unreadable] induction of both innate and adaptive immune responses. Such responses need to be kept under tight[unreadable] control. Immune responses that are delayed or of insufficient vigor can lead to a failure to control infection.[unreadable] On the other hand, excessive or inappropriate inflammation can be harmful or even fatal. The hyperinflammatory[unreadable] responses that characterize sepsis provide a paradigmatic example, as do the more localized[unreadable] inappropriate inflammatory processes associated with arthritis. In addition to signaling the presence of[unreadable] microbial products, the TLR pathway is also involved in signaling the presence of altered or damaged self.[unreadable] A variety of molecular patterns generated during tissue inflammation have been shown to signal through[unreadable] TLR4, the most robustly signaling of the TLRs.[unreadable] We recently discovered a novel endogenous inhibitor of TLR4 signaling in myeloid cells: the TLR4[unreadable] homolog RP105. The central hypothesis underlying these studies is that RP105 acts to mute injurious[unreadable] tissue inflammatory responses through modulation of TLR4 signaling driven by endogenous ligands[unreadable] unmasked by tissue injury. The long-term goal of this research program is to define the molecular[unreadable] mechanisms that underlie dysregulation of tissue inflammatory responses in organ-specific autoimmune[unreadable] diseases such as the autoimmune arthritides. The studies in this proposal will employ genetic approaches[unreadable] to define the role of RP105 (and TLR4) in two well-defined mouse models of microbial productindependent,[unreadable] localized, inflammatory tissue injury: (1) sterile inflammation induced by oil of turpentine; and[unreadable] (2) antibody-induced arthritis.[unreadable]